Interleukin 15 is an essential cytokine for maintenance of memory CD8 T cells and thus plays an important role in immune system homeostasis and in effective vaccination. IL-15 operates through an unusual mechanism whereby IL-15 bound to the high affinity IL-15R1 expressed by one cell type is transpresented to responding memory CD8 T cells expressing a dimeric receptor composed of IL- 2/15R1 and 3C. However, the majority of studies have concentrated on the analysis of IL-15 and memory cells raised through acute immunization or infection, while this proposal will focus on the role of IL-15 in CD8 T cell responses to latent virus infection. The unique characteristics of mouse cytomegalovirus (MCMV)-specific memory CD8 T cells along with preliminary data showing divergent memory dysregulation in IL-15 versus IL-15R1-deficient mice provide the foundation for the proposed studies. Three specific aims will test the hypothesis that IL-15 andIL-15R play opposing roles in regulation of memory CD8 T cells responding to chronic antigen presentation. Aim 1. To determine the key features of IL-15 and IL-15R mediated effects on MCMV-specific memory CD8 T cells. Experiments in this aim will seek to delineate the role of IL-15 and IL-15R1 in proliferation and survival of MCMV-specific CD8 memory T cells in lymphoid and non-lymphoid tissues. In addition, the potential for ongoing recruitment of naive CD8 T cells into the response and the role of IL-15/IL-15R1 in this process will be addressed. These experiments will determine the underlying basis for the unique characteristics of MCMV-specific memory CD8 T cells and delineate the role of IL-15/IL-15R1 in regulation of memory homeostasis. Aim 2. To determine the role of IL-15 and IL15R components in MCMV-specific memory CD8 T cell inflation in lymphoid and non-lymphoid tissues. Our preliminary data suggest that IL-15 and IL-15R1 exert opposing influences on MCMV- specific memory CD8 T cell homeostasis. The basis for this novel dichotomy will be explored in this aim. The components driving expansion will be explored using mixed bone marrow chimeras derived from mice deficient in IL-15, IL15R and IL-2R components. Aim 3. To visualize in situ the influence of IL-15/IL-15R1 on the CD8 T cell response to MCMV infection. MCMV-specific memory cells will be imaged in vivo using in situ tetramer staining in conjunction with CD11c-mCherry reporter mice. These tools will allow us to visualize the effects of IL-15 and IL-15R1 deficiency on immune response anatomy. Overall, these studies will provide a comprehensive view of the role of IL-15/IL-15R in governing memory CD8 T cell dynamics during infection with a clinically relevant pathogen. PUBLIC HEALTH RELEVANCE: This proposal aims to understand the function of the cytokine IL-15 and its receptor in controlling memory CD8 T cells following mouse cytomegalovirus (MCMV) infection. CMV infection is highly clinically relevant since the infection is often the cause of organ rejection following transplantation. In addition, memory CD8 T cell inflation, the process being studied here, results in a highly skewed and restricted T cell repertoire in the elderly, thereby limiting the ability of the individual to respond to other infections.